Transition metal chelate complexes with tetrazole derived Mannich base: Metal dependent architecture and properties

Article abstract of DOI:10.1016/j.poly.2018.05.012

Complexes [Cu₂L₂Cl₄], [NiL₂Cl₂], [PdLCl₂], and [PtLCl₂], where L is a novel ligand from the series of 2-subsituted 5-(α-aminoalkyl)tetrazoles, namely 5-(N,N-dimethylaminomethyl)-2-tert-butyltetrazole, have been synthesized and characterized by IR spectroscopy, thermal analysis and single crystal X-ray analysis. The complexes reported show different coordination geometries of the metals, viz. octahedral for Ni, square pyramidal for Cu, and square planar for Pt and Pd complexes. At the same time, the ligand L demonstrates the same coordination mode in all the complexes. It acts as a chelating ligand coordinated to the metal via two nitrogen atoms, namely the tetrazole ring N⁴ and the dimethylamino N atoms. Complex [PtLCl₂] was found to have promising antiproliferative activity against human cervical carcinoma cells, with IC₅₀ value being average between those of cisplatin and carboplatin. The temperature-dependent magnetic susceptibility measurements of complex [Cu₂L₂Cl₄] revealed that the copper(II) ions were weakly antiferromagnetically coupled showing a coupling constant J of ?2 cm^?1.

Full text of DOI:10.1016/j.poly.2018.05.012

Accepted Manuscript
Transition metal chelate complexes with tetrazole derived Mannich base: metal
dependent architecture and properties
Inna M. Grigorieva, Tatiyana V. Serebryanskaya, Yuri V. Grigoriev, Alexander
S. Lyakhov, Ludmila S. Ivashkevich, Artem S. Bogomyakov, Ludmila G.
Lavrenova, Sergei V. Voitekhovich, Oleg A. Ivashkevich
PII:
S0277-5387(18)30250-X
https://doi.org/10.1016/j.poly.2018.05.012
POLY 13159
DOI:
Reference:
Polyhedron
To appear in:
Received Date:
Accepted Date:
25 March 2018
6 May 2018
Please cite this article as: I.M. Grigorieva, T.V. Serebryanskaya, Y.V. Grigoriev, A.S. Lyakhov, L.S. Ivashkevich,
A.S. Bogomyakov, L.G. Lavrenova, S.V. Voitekhovich, O.A. Ivashkevich, Transition metal chelate complexes with
tetrazole derived Mannich base: metal dependent architecture and properties, Polyhedron (2018), doi: https://
doi.org/10.1016/j.poly.2018.05.012
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Transition metal chelate complexes with tetrazole derived Mannich base:
metal dependent architecture and properties
Inna M. Grigorieva,a Tatiyana V. Serebryanskaya,a Yuri V. Grigoriev,a
Alexander S. Lyakhov,a Ludmila S. Ivashkevich,a Artem S. Bogomyakov,b
Ludmila G. Lavrenova,c Sergei V. Voitekhovich,*a Oleg A. Ivashkevichd
aResearch Institute for Physical Chemical Problems of Belarusian State University,
Leningradskaya 14, 220006 Minsk, Belarus
bInternational Tomography Center, Siberian Branch of the Russian Academy of Sciences,
Institutskaya 3a, 630090 Novosibirsk, Russia
cNikolaev Institute of Inorganic Chemistry, Siberian Branch of the Russian Academy of Sciences,
Acad. Lavrentiev avenue 3, 630090 Novosibirsk, Russia
dBelarusian State University, Nezalezhnasti avenue 4, 220050 Minsk, Belarus
Abstract
Complexes [Cu2L2Cl4], [NiL2Cl2], [PdLCl2], and [PtLCl2], where L is a novel ligand from the
series of 2-subsituted 5-(α-aminoalkyl)tetrazoles, namely 5-(N,N-dimethylaminomethyl)-2-tert-
butyltetrazole, have been synthesized and characterized by IR spectroscopy, thermal analysis and
single crystal X-ray analysis. The complexes reported show different coordination geometries of
the metals, viz. octahedral for Ni, square pyramidal for Cu, and square planar for Pt and Pd
complexes. At the same time, the ligand L demonstrates the same coordination mode in all the
complexes. It acts as a chelating ligand coordinated to the metal via two nitrogen atoms, namely
the tetrazole ring N4 and the dimethylamino N atoms. Complex [PtLCl2] was found to have
promising antiproliferative activity against human cervical carcinoma cells, with IC50 value
being average between those of cisplatin and carboplatin. The temperature-dependent magnetic
susceptibility measurements of complex [Cu2L2Cl4] revealed that the copper(II) ions were
weakly antiferromagnetically coupled showing a coupling constant J of ˗2 cm−1.
Keywords: Metallocomplexes; Tetrazoles; Cytotoxicity; Magnetic properties

1. Introduction
Mannich bases of CH- and NH-acidic azoles (HetH) with general formula Het-CH2NR2 are of
interest due to their wide range of bioactivity [1,2]. Introduction of the aminomethyl group as a
side chain to azoles is used to increase their aqueous solubility and thereby to improve the
bioavailability, that is important for drug design. Moreover, the presence of several donor
heteroatoms in azole rings and additional amino group in α-position of the side chain makes the
above compounds attractive as multidentate ligands, providing diverse coordination modes
including chelating ones. Although direct C- and N-aminomethylation was previously reported
for parent tetrazole and its 1- and 5-monosubstituted derivatives [3,4], very little has appeared in
the literature concerning the coordination chemistry of corresponding Mannich bases. Only the
preparation and structure of copper(II) complexes with N,N-dimethyl-1-(1-methyl-1H-tetrazol-5-
yl)methanamine [5] and 5-aminomethyl-1H-tetrazole [6] have been published.
Herein, we report the preparation, thermal behavior and single crystal X-ray analysis of
copper(II), nickel(II), platinum(II) and palladium(II) chloride complexes with a Mannich base,
namely 5-(N,N-dimethylaminomethyl)-2-tert-butyltetrazole (1). Additionally, magnetic
properties of the synthesized copper(II) complex and antiproliferative activity of the platinum(II)
complex have been also investigated.
2. Experimental section
2.1. Materials and instrumentation
All reagents and solvents were obtained from commercial sources and used without
purification. Elemental analyses for C, H, and N were performed on a FlashEA 1112 analyzer.
13
1H and C NMR spectra were recorded on a Bruker Avance 500 spectrometer at 500 and 125
MHz, correspondingly. The observed chemical shifts were referenced to the solvent signals
(DMSO-d6, δH 2.50, δC 39.43). FT-IR absorption spectra were recorded in the range 4000–400
cm–1 on a Thermo Nicolet Avatar 360 spectrometer. The TG and DSC curves were obtained
using a NETZSCH STA429 thermoanalyzer in a dynamic nitrogen atmosphere (heating rate 10
°C min–1, aluminium oxide, mass 1–3 mg, temperature range from room temperature to 500 °C).
The magnetic susceptibility of copper(II) complex was measured on a polycrystalline sample
using a Quantum Design MPMSXL SQUID magnetometer in the temperature range 5–300 K
with magnetic field of up to 5 kOe. Diamagnetic corrections were made using the Pascal
½
½
2
constants. The effective magnetic moment was calculated as µeff(T) = [(3k/NAµB )χT] ≈ (8χT) .

2.2. Synthesis of the compounds
2.2.1. Synthesis of 5-(N,N-dimethylaminomethyl)-1H-tetrazole (2)
Compound 2 was synthesized following a procedure described in the literature [3]. A mixture
of 1H-tetrazole (10.5 g, 150 mmol), dimethylamine hydrochloride (12.23 g, 150 mmol),
paraformaldehyde (6.9 g, 230 mmol), 5–6 drops of concentrated hydrochloric acid, benzene (75
mL), and nitrobenzene (75 mL) was heated to reflux in Dean-Stark apparatus for 4 h. Then the
reaction mixture was cooled to room temperature and the solvent was decanted. 2-Propanol (250
mL) and solution of sodium hydroxide (6 g, 150 mmol) in water (45 mL) were added to the
residue. The mixture obtained was boiled for 10 min, then filtered while hot, cooled to −15 °С
and held at this temperature for 2 days. Brownish crystals of 2 (Yield 9.86 g, 52 %) were isolated
1
by filtration of the above cold mixture. H NMR δ (ppm): 4.28 (s, 2H, CH2), 2.63 (s, 6H, 2Me);
13C NMR δ (ppm): 153.1 (CN4), 51.3 (CH2), 42.6 (2Me). Anal. Calcd for C4H9N5: C, 37.79; H,
7.13; N, 55.08. Found: C, 37.66; H, 7.20; N, 54.85.
2.2.2. Synthesis of 5-(N,N-dimethylaminomethyl)-2-tert-butyltetrazole (1)
tert-Butyl alcohol (0.70 g, 9.4 mmol) was added dropwise with stirring to a solution of 2 (1.07
g, 8.5 mmol) in conc. sulfuric acid (6 mL). Then the reaction mixture was kept at room
temperature for 1 h, poured into 35 g of ice-water mixture, neutralized with aqueous sodium
hydroxide (25 %, 30 mL), and extracted with benzene (3×20 mL). The combined extract was
dried over anhydrous potassium carbonate, and evaporated to give 1 as yellowish oil (Yield 80
%, 1.20 g). Anal. Calcd for C8H17N5: C, 52.43; H, 9.35; N, 38.22. Found: C, 52.60; H, 9.50; N,
1
13
37.95. H NMR δ (ppm): 3.68 (s, 2H, CH2), 2.13 (s, 6H, 2Me), 1.67 (s, 9H, 3Me); C NMR δ
(ppm): 162.3 (CN4), 63.2 (C), 52.5 (CH2), 44.4 (2Me), 28.6 (3Me). FT-IR (cm–1): 2983 s, 2941 s,
2865 s, 2823 s, 2774 s, 1497 m, 1461 s, 1400 m, 1732 s, 1348 m, 1311 s, 1263 m, 1235 m, 1197
s, 1171 s, 1143 m, 1099 w, 1074 w, 1030 s, 852 m, 828 m, 804 m, 715 m, 703 m, 591 m, 505 w,
497 w.
2.2.3. Synthesis of [Cu2L2Cl4] (3) and [Cu2L2Cl4]·2CHCl3 (3s)
CuCl2·2H2O (106 mg, 0.62 mmol) was added to a solution of 1 (110 mg, 0.62 mmol) in 1,2-
dichloroethane (20 mL). The resulting mixture was stirred at room temperature for 6 h and
filtered to remove unreacted salt. Slow evaporation of the obtained solution at ambient
conditions gave green crystals of complex 3 (Yield 75 %, 147 mg). Anal. Calcd for
C16H34Cl4Cu2N10: C, 30.24; H, 5.39; N, 22.04. Found: C, 30.45; H, 5.18; N, 21.85. FT-IR (cm–1):
3020 m, 2983 s, 2935 s, 2915 s, 2794 w, 1520 m, 1462 s, 1403 m, 1374 s, 1340 m, 1307 s, 1277
m, 1284 m, 1203 s, 1180 s, 1111 m, 1073 w, 1028 s, 995 s, 941 w, 831 s, 809 s, 781 m, 712 m,

594 m, 585 m 478 w, 403 w. Recrystallization of 3 from chloroform–toluene mixture gave green
crystals of solvated complex [Cu2L2Cl4]·2CHCl3, hereinafter referred to as complex 3s.
2.2.4. Synthesis of [NiL2Cl2] (4)
NiCl2·6H2O (74 mg, 0.31 mmol) was added to a solution of 1 (110 mg, 0.62 mmol) in 1,2-
dichloroethane (20 mL). The resulting mixture was stirred at room temperature for 18 h and
filtered to remove unreacted salt. Slow evaporation of the obtained solution at ambient
conditions gave green crystals of complex 4 (Yield 46 %, 71 mg). Anal. Calcd for
C16H34Cl2N10Ni: C, 38.74; H, 6.91; N, 28.23. Found: C, 38.95; H, 7.02; N, 27.98. FT-IR (cm–1):
2984 s, 2922 m, 2884 m, 1530 s, 1469 s, 1445 s, 1380 s, 1350 s, 1313 s, 1274 w, 1242 w, 1224
m, 1189 s, 1162 w, 1118 w, 1030 s, 1005 s, 977 m, 859 s, 830 w, 789 w, 712 w, 609 w, 538 w,
485 m, 409 w.
2.2.5. Synthesis of [PdLCl2] (5)
PdCl2·2H2O (107 mg, 0.5 mmol) was dissolved in 1M HCl aqueous solution (10 mL) under
stirring at 50 °C. To the resulting solution, a solution of 1 (92 mg, 0.5 mmol) in ethanol (5 mL)
was added under stirring, and the reaction mixture was cooled to room temperature. The
precipitate formed was filtered off and recrystallized from hot acetonitrile to give orange crystals
of complex 5 (Yield 78 %, 141 mg). Anal. Calcd for C8H17Cl2N5Pd: C, 26.65; H, 4.75; N, 19.42.
Found: C, 26.80; H, 4.80; N, 19.22. FT-IR (cm–1): 1533 m, 1466 s, 1432 m, 1406 w, 1310 m,
1268 w, 1238 m, 1203 m, 1180 vs, 333 s br.
2.2.6. Synthesis of [PtLCl2] (6)
A solution of 1 (62 mg, 0.34 mmol) in ethanol (5 mL) was added to a solution of K2PtCl4 (140
mg, 0.34 mmol) in distilled water (5 mL) under stirring. The resulting mixture was stirred at
room temperature for 6 h. The precipitate formed was filtered off and recrystallized from
acetonitrile to give yellow crystals of complex 6 (Yield 75 %, 114 mg). Anal. Calcd for
C8H17Cl2N5Pt: C, 21.39; H, 3.81; N, 15.59. Found: C, 21.20; H, 3.90; N, 15.44. FT-IR (cm–1):
2988 s, 2938 s, 2885 w, 1537 m, 1464 s, 1406 w, 1373 s, 1346 сл, 1310 s, 1271 w, 1235 m, 1205
m, 1179 s, 1147 w, 1111 w, 1021 m, 949 m, 852 s, 823 m, 786 w, 696 w, 601 m, 550 m, 517 w,
457 w, 412 w, 333 w.
2.3. X-ray structure determinations of complexes 3, 3s and 4–6
Suitable single crystals of synthesized complexes were directly picked up from the reaction
mixture. Single crystal X-ray data were collected on a SMART Apex II diffractometer using
graphite monochromated Mo-K radiation ( = 0.71073 Å) at a temperature of 100 K. The
structures were solved by direct methods (SIR2014)[7] and refined on F2 by the full-matrix least
squares technique (SHELXL 2014) [8]. The intensities were corrected for absorption. Non-

hydrogen atoms were refined anisotropically. The hydrogen atoms were placed in calculated
positions and refined in a “riding” model, with Uiso(H) = 1.5Ueq(C) for the methyl groups and
Uiso(H) = 1.2Ueq(C) for the methylene groups. Molecular graphics was performed with the
programs ORTEP-3 for Windows [9] and PLATON [10]. X-ray powder diffraction data of
polycrystalline complexes 3–6 were used to control their purity. The powder patterns were
recorded with an EMPYREAN diffractometer (PANalytical, Netherlands) using Cu-Ka radiation
(Ni-filter) at room temperature (Figures S7–S11).
2.4. Antiproliferative activity assay of complex 6
Antiproliferative activity of platinum(II) complex [PtLCl2] was measured against HeLa cell
line using trypan-blue exclusion assay as described earlier [11]. Briefly, HeLa cells (human
cervical carcinoma) were cultured as a monolayer in culture flasks covered with 199 medium
(RIEM) supplemented with 10 % fetal calf serum (RIEM) and 100 lg/mL kanamycin. Stock 10–2
M solutions of tested compound was freshly prepared in dimethylsulfoxide (DMSO), and then
dilutions in distilled water from 10–4 to 10–6 M were made. On the day of the experiment, 50, 100
or 200 µL of drug dilutions were added into the flasks with cell monolayer at final
concentrations of 0–100 µM. The cells were incubated at 37.0 °C for 48 h. Then treated and
control cell monolayers were versenized, and viable cells were counted using trypan-blue
exclusion on a haemocytometer [12]. IC50 values (drug concentration required to inhibit 50% of
cell growth) were calculated from three independent experiments using regression analysis of the
data received.
3. Results and discussion
3.1. Synthesis
5-(N,N-Dimethylaminomethyl)-2-tert-butyltetrazole (1) was obtained by two-step synthesis
from parent 1H-tetrazole (Scheme 1). At the first stage, C-aminomethylation of 1H-tetrazole was
performed by action of dimethylamine hydrochloride and paraformaldehyde under reflux in
benzene–nitrobenzene solution [3]. In this way 5-(N,N-dimethylaminomethyl)-1H-tetrazole (2)
was obtained in 52 % yield. Subsequent alkylation of 2 was carried out by the action of tert-butyl
alcohol in concentrated sulfuric acid giving tetrazole 1 in 80% yield.
Scheme 1. Synthesis of target ligand 1.

Acidic approach [13] was chosen for the alkylation in connection with recent success in
adjusting the regioselectivity of N-functionalization of azoles using such approach [14–18]. In
particular, it presents an efficient tool for introducing the lipophilic tert-butyl group into the N2
position of the tetrazole cycle [13, 18]. The regioselectivity of alkylation of 5-R-tetrazoles is
explained by the protonation of the tetrazole ring at the N4 atom, resulting in the formation of 5-
R-1H-4H-tetrazolium cations, in which only equivalent N2 and N3 atoms are accessible for attack
by carbenium cations generated from the alkylation agents, like olefins and alcohols [13, 19].
The interaction of two positively charged entities seems rather unusual at first sight, however,
quantum chemical calculations for a series of the above tetrazolium cations revealed that they
show substantial electron density localized on N2 and N3 atoms [20]. The same mechanism is
proposed for tert-butylation of 1 (Scheme 2). In this case, however, primary protonation at the
amino N atom should be taken into account as well. Therefore, cation A acts as an alkylation
substrate in highly acidic medium, such as sulfuric acid. Interaction of A with the tert-butyl
cation, generated from the alcohol, leads to dication B. The latter undergoes deprotonation under
alkaline work-up of reaction mixture forming 2,5-disubstituted tetrazole 1. The obtained
1
compound 1 was identified based on H and 13C NMR data. In particular, 13C NMR chemical
shift of the tetrazole ring C5 atom of 162.3 ppm is in accordance with the data on related 2,5-
disubstituted tetrazoles [17].
Scheme 2. Plausible mechanism of regioselective alkylation of 2.
Tetrazole 1 belongs to 2,5-disubstituted tetrazoles, which show the weakest basicity of
heteroring nitrogen atoms among neutral tetrazoles. Moreover, the presence of a substituent at
the tetrazole ring C5 atom obstructs the binding of metal cations with the most donor nitrogen
atom N4 by steric reason. Hence, successful complexation of 2,5-disubstituted tetrazoles needs
the use of weakly coordinating solvents and sometimes the removal of competitive ligands like
water [21]. Obviously, the presence of highly basic amino group in chelating position in relation
to N4 endocyclic atom in ligand 1 significantly enhances its complexing ability in comparison
with 2,5-dialkyltetrazoles. We found that this ligand reacted with copper(II) chloride dihydrate in
1,2-dichloroethane to give complex [Cu2L2Cl4] (3) (Scheme 3). Its recrystallization from
chloroform–toluene mixture generated crystals of solvated complex [Cu2L2Cl4]·2CHCl3 (3s).

Scheme 3. Complexation of ligand 1.
Nickel(II) chloride hexahydrate reacted with ligand 1 in 1,2-dichloroethane giving [NiL2Cl2] (4).
Complexes [PdLCl2] (5) and [PtLCl2] (6) were obtained by reaction of tetrazole 1 with
palladium(II) chloride dihydrate in 1M HCl aqueous solution or with potassium
tetrachloridoplatinate(II) in water/ethanol mixture, respectively.
Thermal analyses of the synthesized complexes were performed from room temperature to
500 °C to examine their thermal stability. Thermogravimetric (TG) and differential scanning
calorimetry (DSC) curves of the compounds are presented in Figs. S1–S5. Thermal stability of
complexes 3, 4, 5, and 6 strongly depends upon the nature of the metal, increasing in the order
Cu < Ni < Pd < Pt. The first stage of their thermolysis proceeds in the endothermic mode, with a
peak located at 150, 190, 222 and 288 °C for complexes 3, 4, 5, and 6, respectively. Solvated
complex 3s loses solvate molecules above 90 °C (endothermic peak of this process is located at
107 °C) to give complex 3. This conclusion follows from X-ray powder pattern of the sample
obtained from complex 3s by its thermal treatment at 100 °C, and also from the same thermal
behavior of complexes 3 and 3s above 120 °C (Figs. S1, S2).
3.2. Crystal structures description
Crystal structures of complexes 3, 3s, and 4–6 were obtained from single crystal X-ray data
collected at a temperature of 100 K. Crystal data, data collection, and structure refinement details
for the compounds are gathered in Table 1. All they did not reveal phase transitions in the
temperature range 100–296 K.

Table 1. Main crystal data and structure refinement details for complexes 3, 3s and 4–6.
Complex 3
Complex 3s
Complex 4
Complex 5
Complex 6
C8H17Cl2N5Pt
449.25
Formula
C16H34Cl4Cu2N10 C18H36Cl10Cu2N10
C16H34Cl2N10Ni C8H17Cl2N5Pd
Formula weight
T (K)
635.41
100(2)
874.15
496.14
360.56
100(2)
100(2)
100(2)
100(2)
Crystal system
Space group
Triclinic
Monoclinic
P21/c
Monoclinic
P21/n
Orthorhombic
Pbca
Orthorhombic
Pbca
ꢀ
P
1
Crystal size (mm) 0.32×0.29×0.26
0.26×0.16×0.08
10.8243(3)
11.8529(3)
27.9693(7)
90
0.16×0.15×0.08 0.46×0.46×0.20
0.23×0.20×0.06
10.61560(10)
11.3826(2)
22.1138(3)
90
a (Å)
b (Å)
c (Å)
α (°)
10.77560(10)
10.86180(10)
12.00230(10)
87.0170(4)
11.37100(10)
10.12770(10)
11.89850(10)
90
10.6319(5)
11.3462(6)
22.1501(11)
90
89.9926(5)
70.2578(4)
1320.19(2)
2
92.6177(15)
90
117.9931(5)
90
90
90
β (°)
90
90
γ (°)
V (Å3)
3584.70(16)
4
1209.94(2)
2
2672.0(2)
8
2672.08(6)
8
Z
Dc (g cm–3 )
µ (mm–1)
Measured refls.
1.598
1.620
1.362
1.793
2.233
2.041
1.960
1.046
1.771
10.885
20864
2472
32776
33710
15160
21483
2447
Independent refls. 8735
8220
2391
Rint
0.0124
0.0271
0
0.0178
43
0.0155
0
0.0233
0
Restraints
Parameters
0
299
371
170
150
150
R1/wR2[I >2σ(I)] 0.0163/0.0450
R1/wR2[all data] 0.0172/0.0455
0.0432/0.1138
0.0516/0.1176
1.051
0.0396/0.1064
0.0438/0.1102
1.017
0.0228/0.0722
0.0230/0.0723
1.079
0.0174/0.0446
0.0208/0.0459
1.006
Goodness-of-fit
0.997
3.2.1. Complexes [Cu2L2Cl4] (3) and [Cu2L2Cl4]·2CHCl3 (3s)
Complex and solvated complex include binuclear complex molecules of the
composition Cu2L2Cl4 (L is ligand 1). The structures of complex molecules in and were
found to be similar and therefore the same atom-numbering scheme for them was used in
the present work (Fig. 1). Whereas complex is triclinic (the space group ), complex
crystallizes in the monoclinic space group P21/c. In both compounds, there is one
complex molecule in the asymmetric unit, including two independent ligands L. In
complex , the asymmetric unit contains additionally two chloroform molecules. All the
atoms of the compounds occupy general positions.
3
3s
3
3s
3
P
1
3s
3s

Fig. 1. Binuclear complex molecule in the crystal structure of 3, with the atom-numbering
scheme (the same atom-numbering is used for complex molecule of 3s). Displacement ellipsoids
are drawn at the 50 % probability level. The hydrogen atoms are shown as spheres of arbitrary
radii.
In complex molecules of 3 and 3, the copper atoms Cu1 and Cu2 are linked together by
double chlorine bridge at the expense of Cl2 and Cl3 atoms. Each copper atom is bonded to
one ligand L through the tetrazole ring N4 and the dimethylamino N atoms, so both independent
ligands L show chelating mode with five-membered chelate rings.
Coordination environment of Cu1 and Cu2 atoms forms considerably distorted square
pyramids, with τ-descriptors [22] for penta-coordination of 0.37 (Cu1) and 0.26 (Cu2) in
complex 3, and respectively 0.33 and 0.31 in complex 3s (τ = 0 for an ideal square pyramid and τ
= 1 for an ideal trigonal bipyramid). Whereas all basal bonds are usual in both compounds, the
apical bonds Cu1–Cl3 and Cu2–Cl2 are significantly elongated and can be considered as semi-
coordinated (Table 2). As a result of considerable distortion of the square pyramids, the mean
deviation of the basal atoms from their least squares planes show rather large values of 0.3062(3)
Å (Cu1) and 0.2448(3) Å (Cu2) in complex 3, and respectively 0.3094(13) and 0.2480(13) Å in
complex 3s. The dihedral angle between the basal planes of two pyramids is 14.856(17)° in 3
and 15.13(6)° in 3s.

Table 2. Coordination bond lengths (Å) and angles (°) in complexes 3 and 3s.
Complex 3
Complex 3s
Cu1 polyhedron
Cu1–N14
Cu1–N15
2.0232(7)
2.1013(7)
2.2331(2)
2.2584(2)
2.7592(2)
79.66(3)
150.10(2)
92.24(2)
95.95(2)
2.004(3)
2.094(3)
2.2313(9)
2.2680(9)
2.8192(10)
79.69(12)
150.83(9)
92.77(9)
95.46(9)
170.83(9)
95.16(3)
88.22(10)
86.65(9)
119.68(3)
85.42(3)
Cu1–Cl1
Cu1–Cl2
Cu1–Cl3
N14–Cu1–N15
N14–Cu1–Cl1
N15–Cu1–Cl1
N14–Cu1–Cl2
N15–Cu1–Cl2
Cl1–Cu1–Cl2
N14–Cu1–Cl3
N15–Cu1–Cl3
Cl1–Cu1–Cl3
Cl2–Cu1–Cl3
172.14(2)
94.731(8)
89.38(2)
86.13(2)
118.988(8)
87.316(7)
Cu2 polyhedron
Cu2–N24
Cu2–N25
2.0076(7)
2.1006(7)
2.2154(2)
2.2803(2)
2.7443(2)
79.49(3)
153.69(2)
93.88(2)
90.35(2)
169.01(2)
97.098(8)
99.74(2)
90.35(2)
105.773(8)
87.249(7)
1.993(3)
2.102(3)
2.2287(9)
2.2842(9)
2.6608(9)
79.49(11)
151.86(9)
93.46(8)
91.16(9)
170.25(8)
96.11(3)
100.09(8)
90.02(8)
107.17(3)
88.93(3)
Cu2–Cl4
Cu2–Cl3
Cu2–Cl2
N24–Cu2–N25
N24–Cu2–Cl4
N25–Cu2–Cl4
N24–Cu2–Cl3
N25–Cu2–Cl3
Cl4–Cu2–Cl3
N24–Cu2–Cl2
N25–Cu2–Cl2
Cl4–Cu2–Cl2
Cl3–Cu2–Cl2
Cu–Cl–Cu bridges
Cu1–Cl2–Cu2
Cu1–Cl3–Cu2
Cu1···Cu2
86.118(7)
85.347(7)
3.434(3)
87.17(3)
83.15(3)
3.4100(5)
The tetrazole rings show the feature, observed often enough in complexes of 2- and 2,5-
substituted tetrazoles, namely formally single bonds N2–N3 are shorter that formally double
bonds N3–N4. In two rings N11–C15 and N21–C25, the lengths of these bonds are N2–
N3 = 1.3162(9)/1.3118(10), N3–N4 = 1.3254(9)/1.3231(10) Å in complex 3, and N2–N3 =
1.303(4)/1.314(4), N3–N4 = 1.325(4)/1.322(4) Å in 3s.
Both complexes reveal non-classic intramolecular hydrogen bonds C16–H16A···Cl3
[hydrogen bond geometry in 3/3s: D···A = 3.3026(8)/3.329(4) Å, D–H···A = 120/121°] (Fig. 2).

In complex 3s, there are additional non-classic hydrogen bonds of chloroform H atoms, binding
chloroform molecules with complex molecules. These are bifurcate bonds C1–H1···Cl3
[D···A = 3.552(4) Å, D–H···A = 143°] and C1–H1···Cl4 [D···A = 3.525(5) Å, D–H···A = 140°]
of one chloroform molecule, and the bonds C2–H2···Cl4a of another molecule [D···A = 3.518(4)
Å, D–H···A = 145°; symmetry code: (a) 1–x, 1–y, 1–z].
Fig. 2. Crystal packing of complexes 3 (top) and 3s (bottom), viewed along the a axis. Dashed
lines show hydrogen bonds. Only the hydrogen atoms participating in hydrogen bonds are
shown.

Although complexes 3 and 3s crystallize in different space groups and have different unit cell
dimensions, nevertheless similar features in their crystal packing are observed. In both
compounds, we can select “layers” of complex molecules, parallel to the ac plane in complex 3
and the ab plane in complex 3s. A side view of such “layers” is provided by Fig. 2. It is clearly
seen that the arrangement of complex molecules in the “layers” is rather similar in both
compounds. As a result, the unit cell dimensions a and c of 3 are close to respectively a and b of
3s. In solvated complex, chloroform molecules are located on both sides of each “layer” and are
hydrogen-bonded to its complex molecules. These structural features allow to explain easy
transformation of complex 3s to complex 3 at about 100 °C.
3.2.2. Complex [NiL2Cl2] (4)
Complex 4 crystallizes in the monoclinic space group P21/n, with two formula units in the unit
cell. The compound presents a mononuclear complex, in which the nickel atom lies on the
inversion centre. In crystals of 4, ligand molecule L is disordered over two positions, with site
occupancy factors 0.9044(19) (site A) and 0.0956(19) (site B). Fig. 3a shows the complex
molecule, in which ligand L occupies site A, whereas Fig.3b illustrates both sites together. It
should be noted that there is one non-disordered atom in ligand L, viz the dimethylamino
nitrogen atom N5.
(a)
(b)
Fig. 3. (a) Complex molecule of 4 with ligand L being in high-occupancy site A [the atom-
numbering is given for the asymmetric unit; unlabeled atoms are related to the labeled ones by
the symmetry operation: 1–x, 1–y, –z; displacement ellipsoids are drawn at the 50% probability
level; the hydrogen atoms are shown as spheres of arbitrary radii]. (b) Comparison of sites A (the
bonds are shown as solid lines) and B (the bonds are shown as dashed lines) of disordered ligand
L in complex 4 [the hydrogen atoms are omitted for clarity].

Further, structural description of complex 4 is given only for high-occupancy site A of ligand
L (the atom-numbering of L includes “A”).
The nickel atom is surrounded by two chlorine atoms and two ligands L, coordinated in
chelate mode via the tetrazole ring N4 and the dimethylamino nitrogen atoms to form a five-
membered chelate ring. Two chlorine and four nitrogen atoms form around the nickel atom a
distorted octahedron, with chlorine atoms in the axial positions. Whereas Ni–Cl bonds are
elongated, all equatorial Ni–N bonds show usual lengths, namely Ni1–Cl1 = 2.4302(6), Ni1–
N4A = 2.062(2), and Ni1–N5 = 2.241(2) Å. Among the valence angles around the nickel atom,
the chelate angle N4A–Ni1–N5 of 78.94(8)° is the smallest angle. All other coordination angles
are in the range of 87.42(5)–101.06(8)° or equal to 180°.
There are no hydrogen bonds in the crystal structure of complex 4. Its crystal packing, shown
in Fig. 4, is stabilized only by van der Waals interactions.
Fig. 4. Crystal packing of 4, viewed along the b axis. Hydrogen atoms are omitted for clarity.
3.2.3. Complexes [PdLCl2] (5) and [PtLCl2] (6)
Complexes 5 and 6 were found to be isomorphous, crystallizing in the orthorhombic space
group Pbca with eight formula units in the unit cell. The same asymmetric unit and the same
atom-numbering schemes were used here for these two compounds. They present mononuclear
complexes, whose molecular structure is illustrated in Fig. 5 for chloride complex 5 as an
example.

The metal atoms are surrounded by two chlorine atoms and one ligand molecule L,
coordinated in a chelate mode through the tetrazole ring N4 and the dimethylamino N5 nitrogen
atoms. The chlorine and nitrogen atoms form around the metal atoms distorted coordination
squares. Coordination characteristics of 5 and 6 are given in Table 3.
Fig. 5. Molecular structure of complex 5, with the atom-numbering scheme. Displacement
ellipsoids are drawn at the 50% probability level. The hydrogen atoms are shown as spheres of
arbitrary radii.
Table 3. Coordination bond lengths (Å) and angles (°) in complexes 5 and 6.
Pd(II) complex 5
1.992(3)
Pt(II) complex 6
1.967(3)
(Pd1/Pt1)–N4
(Pd1/Pt1)–N5
2.097(3)
2.084(3)
(Pd1/Pt1)–Cl1
2.2809(9)
2.3007(8)
81.96(10)
173.43(8)
92.47(7)
2.2845(10)
2.3037(8)
81.63(11)
173.56(9)
92.74(7)
(Pd1/Pt1)–Cl2
N4–(Pd1/Pt1)–N5
N4–(Pd1/Pt1)–Cl1
N5–(Pd1/Pt1)–Cl1
N4–(Pd1/Pt1)–Cl2
N5–(Pd1/Pt1)–Cl2
Cl1–(Pd1/Pt1)–Cl2
94.27(8)
95.06(9)
175.56(7)
91.15(3)
176.27(7)
90.48(3)
As can be seen from Table 3, all coordination bonds (Pd/Pt)–Cl and (Pd/Pt)–N are usual.
Coordination cores (Pd/Pt)N2Cl2 are substantially planar, with mean deviations of their atoms
from corresponding least-squares planes of 0.0244(12) Å in complexes 5 and 0.0217(12) Å in
complex 6. The valence angles N4–(Pd1/Pt1)–N5 are close to those in complexes 3, 3s and 4,
being lower than 90° as a result of their including in five-membered chelate cycles.
In the crystal structures of 5 and 6, there are only non-classic intermolecular hydrogen bonds

C6–H6A···Cl2b between the methylene H and Cl atoms of neighboring complex molecules
[hydrogen bond geometry (Pd/Pt): D···A = 3.487(3)/3.504(4)°, D–H···A = 149/151°] (symmetry
code (b) as in Fig. 6). These bonds are responsible for formation of centrosymmetric dimers,
shown in Fig. 6.
Fig. 6. Hydrogen-bonded centrosymmetric dimer in the crystal structure of 5. Symmetry code
(b): 1–x, 1–y, 1–z.
3.3 Magnetic properties of complex 3
The presence of separated Cu2Cl4 units in complex 3 determines the interest in the magnetic
investigation of the compound. Its magnetic properties were investigated by temperature-
dependent magnetic susceptibility measurements in the temperature range between 2 and 300 K.
Fig. 7 shows the experimental data and the theoretical fit in the form of µeff vs. T. The effective
magnetic moment µeff is of 2.56 µB at 300 K, and remains nearly constant with decreasing
temperature down to 70 K. Upon further lowering the temperature, µeff rapidly decreases to
2.09 µΒ at 5 K. The µeff values in the temperature range 300–70 K are in a good agreement with a
theoretical value of 2.63 µB for two copper(II) ions with g-factor of 2.15. The decreasing of the
µeff below 70 K indicates the presence of weak antiferromagnetic exchange interactions between
spins of the copper(II) cations. The model of exchange-coupled dimer (spin Hamiltonian H = –
2JS1S2) was used for the analysis of the experimental µeff(T) dependence. The best fit was
reached with g-factor of 2.08 and exchange interaction parameter J of –2.0 cm–1.

Fig. 7. Temperature dependence of µeff for compound 3 (•) per dinuclear unit. The red solid line
represents the best theoretical fit.
Several attempts have been made to establish the correlations between structural and magnetic
properties of binuclear copper(II) complexes with Cu(µ-Cl)2Cu core [23–26]. It has been shown
that exchange coupling constant J is determined by such structural parameters as coordination
geometry of copper atoms, the bridging angles Cu–Cl–Cu, and the Cu···Cu distances. In
complexes with square-pyramidal coordination of two copper atoms, magneto-structural
correlations were found to depend on the relative orientation of square pyramids.
Compound 3, investigated in the present work, belongs to the group of complexes, in which
copper(II) square pyramids share a base-to-apex edge and their basal planes are approximately
parallel. In such complexes, super exchange pathway between the metal centres will take place
mainly through a π* type interaction between the dx2–y2 orbitals of Cu2+ ions and the p-orbitals of
chlorine bridging ligand as shown using extended Hückel calculations [24]. For an ideal
geometry with a square core, the overlap integral between the former orbitals would be zero.
However, due to deviations of Cu(µ-Cl)2Cu core from the ideal square, these complexes usually
show antiferromagnetic or ferromagnetic coupling with relatively small coupling constants (–10
< J < +10 cm–1) [25]. A strong correlation has been found between J value and the ϕ/R ratio,
where ϕ is the Cu–Cl–Cu bridging angle and R is the longest Cu–Cl distance in the chloride
bridge [26]. It was estimated that the exchange interaction is ferromagnetic if ϕ/R ratio lies
within the range 31–34.5 deg·Å–1, otherwise it is antiferromagnetic. In the case of complex 3,
where the copper(II) centres Cu1 and Cu2 are not identical, two ϕ/R values can be calculated,

namely ϕ/R = 30.9 deg·Å–1 [for R(Cu1–Cl3), ϕ(Cu1–Cl3–Cu2)] and ϕ/R = 31.4 deg·Å–1 [for
R(Cu2–Cl2), ϕ(Cu2–Cl2–Cu1)]. Both calculated values of ϕ/R are very close to the lower limit
of 31 deg·Å–1 of the above interval. Because the correlation J(ϕ/R) presents only an
approximation, both positive and negative small coupling constants J should be expected for
complex 3 from this correlation. Therefore, small experimental value J of –2.0 cm–1, obtained for
complex 3, does not contradict the above empirical magneto-structural correlation.
3.4. Antiproliferative activity of complex 6
In the last decade, various tetrazole-containing platinum(II) and platinum(IV) complexes
attracted a great deal of attention as promising antitumor agents [11, 27–32]. Due to variety of
possible substitutes and the ability of the tetrazole ring to decrease toxicity of modifying
medicines, tetrazole-based ligands have been utilized to design new generation of perspective
platinum(II) complexes with lower toxicity [30, 31], increased water solubility [31, 32], and the
ability to overcome tumor resistance to the common platinum drugs [28–31].
In our previous works, we have been focused on antiproliferative activity of platinum(II)
complexes with N-substituted tetrazoles as carrier ligands. In a good agreement with classic SAR
rules, cytotoxicity of such complexes turned out to be dependent on their geometry and
lipophilicity. The most active species cis-Pt(5-amino-2-tert-butyltetrazole)2Cl2 appeared to be at
least as active as cisplatin in a number of cisplatin-sensitive cancer cell lines and also able to
overcome cross-resistance in cisplatin-resistant cell lines [31]. However, cis-isomeric platinum
complexes with N-substituted tetrazoles were found to be prone to thermal isomerization both in
the solid state and in the solution. Therefore, we were interested in designing structurally related
complexes with fixed cis geometry of the platinum(II) coordination center.
To this aim, complex 6 was obtained and its antiproliferative activity was investigated in
human cervical carcinoma cell line (HeLa) using trypan-blue exclusion assay. Cisplatin and
carboplatin were included into the assay as a positive control. The determined IC50 values are
summarized in Figure S6. Tetrazole complex 6 demonstrates promising activity, with IC50 value
of 3.9 µM being average between those of cisplatin (0.6 µM) and carboplatin (12.5 µM). Free
ligand is inactive, with IC50 exceeding 100 µM. It should be noted that complex 6 demonstrated
lower activity in comparison with parent cis-Pt(5-amino-2-tert-butyltetrazole)2Cl2, which
showed IC50 of 0.9 µM in HeLa cell line [31], but appeared to be more active than corresponding
trans-isomeric complex trans-Pt(5-amino-2-tert-butyltetrazole)2Cl2 with IC50 of 5.6 µM in HeLa
cell line [11].

4. Conclusion
Novel tetrazole derived Mannich base, namely 5-(N,N-dimethylaminomethyl)-2-tert-
butyltetrazole, was synthesized and used as ligand to obtain coordination compounds with
Cu(II), Ni(II), Pd(II), and Pt(II) chlorides. As was expected, tetrazole ligands in all the
complexes are coordinated by metals in chelate fashion via N4 atom of the tetrazole heteroring
and N atom of the dimethylamino group. However, the composition of the complexes,
coordination environment of metals and their coordination polyhedra were found to be different,
depending on the nature of the metal. All the complexes have molecular structure. Thermal
stability of the synthesized complexes increases in the following order: Cu < Ni < Pd < Pt.
Platinum(II) chloride complex was found to have promising antiproliferative activity against
human cervical carcinoma cells, with IC50 value being average between those of cisplatin and
carboplatin. Binuclear copper(II) complex shows weak antiferromagnetic coupling between
metal cations.
Acknowledgements
This work was supported by Belarusian Republican Foundation for Fundamental Research (grant
X16P-009).
Appendix A. Supplementary material
CCDC deposition numbers: 1831886, 1831887, 1831888, 1831889, and 1831890 contain the
supplementary crystallographic data for complexes 3, 3s, 4, 5 and 6, respectively. These data can
be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44)
1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
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Synopsis
Novel tetrazole derived Mannich base is coordinated with transition metal chlorides in chelate fashion.
The composition of the complexes and coordination geometry of the metals are different, depending on
the nature of the metal. [PtLCl2]have promising antiproliferative activity against human cervical
carcinoma cells. In [Cu2L2Cl4] copper(II) ions are weakly antiferromagnetically coupled.